Nicotinic acetylcholine receptors (nAChR) are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channels increases. Nicotinic alpha 7 receptor (alpha 7 nAChR) forms a homopentameric channel in vitro that is highly permeable to calcium cations. Each alpha 7 nAChR has four transmembrane domains, known as M1, M2, M3, and M4. The M2 domain has been suggested to form the wall lining the channel. Sequence alignment shows that the alpha 7 nAChR is highly conserved during evolution. The M2 domain that lines the channel is identical in protein sequence from chick to human. Alpha 7 nAChR is described by, Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol. 290(3), 237-246.
The alpha 7 nAChR channel is expressed in various brain regions and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning, memory and attention (Levin et al., Psychopharmacology (1998), 138, 217-230). Alpha 7 nAChR are localized on both presynaptic and postsynaptic terminals and have been suggested to be involved in modulating synaptic transmission. Agonists of alpha 7 nAChR have been shown to improve attention and cognition in Alzheimer's and attention deficit disorder conditions (Wilens et al., Am. J. Psychiatry (1999), 156(12), 1931-1937).
The analgesic effects of nicotine have long been known. Agonists of the alpha 7 nAChR receptor have been shown to modulate production of pro-inflammatory cytokines, including interleukins (ILs), tumor necrosis factor (TNF) alpha, and high-mobility group box (HMGB-1), and to inhibit inflammatory signalling in the CNS (de Jonge et al., Br. J. Pharmacol. (2007), 1-15). The alpha 7 nAChR receptor has a role in modulating CNS pain transmission, and alpha 7 nAChR agonists have shown an antinociceptive effect in an acute pain model (Damaj et al., Neuropharmacol.(2000) 39, 2785-2791.
Since acetylcholine (ACh) is an endogenous agonist of alpha 7 nAChR, agonists that act at the same site as ACh can stimulate and possibly block receptor activity through desensitization and competitive blockade processes (Forman et al., Biophysical J.(1988), 54(1), 149-158) and lead to prolonged receptor inactivation (Buisson et al., J. Neurosci.(2001), 21(6), 1819-1829). Desensitization limits the duration that the ion channel remains activated during agonist application. Thus the enhancement of Alpha 7 nAChR activity provided by such agonists will also increase competition with ACh, and therefore limit the usefulness of agonists as drugs.
Positive allosteric modulators of the nicotinic alpha 7 receptor channel enhance the activity of ACh and other nicotinic alpha 7 receptor agonists. Positive allosteric modulators activate alpha 7 nAChR when sufficient ACh is present in the central nervous system. Positive allosteric modulators of alpha 7 nAChRs thus are useful for treatment of CNS, pain and inflammatory diseases or conditions, to regulate CNS functions such as cognition, learning, mood, emotion and attention, and control production of pro-inflammatory cytokines associated with pain and inflammatory conditions. There is accordingly a need for new positive allosteric modulators of the nicotinic alpha 7 receptor channel.